• Shinichiro Nakajima, Hiroyuki Uchida, Robert R Bies, Fernando Caravaggio, Takefumi Suzuki, Eric Plitman, Wanna Mar, Philip Gerretsen, Bruce G Pollock, Benoit H Mulsant, David C Mamo, and Ariel Graff-Guerrero.
• Geriatric Mental Health Division, Centre for Addiction and Mental Health, Toronto, Canada; Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan; hiroyuki.uchida.hu@gmail.com.
• Schizophr Bull. 2016 Jan 1; 42 (1): 212-9.

BackgroundPopulation pharmacokinetics can predict antipsychotic blood concentrations at a given time point prior to a dosage change. Those predicted blood concentrations could be used to estimate the corresponding dopamine D2/3 receptors (D2/3R) occupancy by antipsychotics based on the tight relationship between blood and brain pharmacokinetics. However, this 2-step prediction has never been tested.MethodsTwo blood samples were collected at separate time points from 32 clinically stable outpatients with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; mean ± SD age: 60.1 ± 7.3 years) to measure plasma concentrations of olanzapine or risperidone at baseline. Then, subjects underwent a dose reduction of olanzapine or risperidone and completed a [(11)C]-raclopride positron emission tomography scan to measure D2/3R occupancy in the putamen. The plasma concentration at the time of the scan was predicted with the 2 samples based on population pharmacokinetic model, using NONMEM. D2/3R occupancy was then estimated by incorporating the predicted plasma concentration in a hyperbole saturation model. The predicted occupancy was compared to the observed value.ResultsThe mean (95% CI) prediction errors for the prediction of D2/3R occupancy were -1.76% (-5.11 to 1.58) for olanzapine and 0.64% (-6.18 to 7.46) for risperidone. The observed and predicted D2/3R occupancy levels were highly correlated (r = 0.67, P = .001 for olanzapine; r = 0.67, P = .02 for risperidone).ConclusionsD2/3R occupancy levels can be predicted from blood drug concentrations collected prior to dosage change. Although this 2-step model is subject to a small degree of error, it could be used to select oral doses aimed at achieving optimal D2/3R occupancy on an individual basis.© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

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